Human reproduction
Folic acid is an important nutrient for women who may become pregnant, because a woman's blood levels of folate fall during pregnancy due to an increased maternal RBC synthesis in the first half of the pregnancy and fetal demands in the second half.
Neural tube defects (NTDs) result in malformations of the spine (spina bifida), skull, and brain (anencephaly). The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception. The protective effect of folate during pregnancy goes beyond NTDs. Supplementation with folic acid has been shown to reduce the risk of congenital heart defects, cleft lip, limb defects, and urinary tract anomalies.
Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of some serious birth defects. Having enough folic acid supplements in the months before pregnancy is very important to prevent neural tube defects. Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The RDA for folate equivalents for pregnant women is 600-800 micrograms, twice the normal RDA of 400 micrograms for women who are not pregnant.
A study published by Milunski et al. has indicated that women who took folic acid supplements during the course of pregnancy can dramatically reduce the prevalence of infant neural tube defects by 3.9 times. The prevalence had dropped from 3.5 to 0.9 defects per 1000 births.
Although the recommended folic acid intake for women planning for pregnancy is 400 micrograms per day, the mechanisms and reasons why folic acid prevents birth defects is unknown. It is hypothesized that the insulin-like growth factor 2 gene is differentially methylated and these changes in IGF2 result in improved intrauterine growth and development. Folate deficiency in the mother increases homocysteine level in the blood which may lead to spontaneous abortion and pregnancy complications such as placental abruption and preeclampsia.
Folic acid may also reduce chromosomal defects in sperm to some extent, which may be relevant for men considering to father a child. A benefit is indicated even for more than 700 mcg folate per day,
Folic acid supplements may even protect the fetus against disease when the mother is battling a disease or taking medications or smoking during pregnancy.
Heart disease
An estimated 13,500 deaths occur annually due to folate deficiency's effect on coronary artery disease and the risk of ischemic heart disease and stroke has been reduced by 15% since folate fortification regulations were enforced. Adequate concentrations of folate, vitamin B12, or vitamin B6 may decrease the circulating level of homocysteine, an amino acid normally found in blood. There is evidence that an elevated homocysteine level is an independent risk factor for heart disease and stroke.
The evidence suggests that high levels of homocysteine may damage coronary arteries or make it easier for blood clotting cells called platelets to clump together and form a clot.
However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce risk of heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good.
As of 2006, studies have shown that giving folic acid to reduce levels of homocysteine does not result in clinical benefit. One of these studies suggests that folic acid in combination with B12 may even increase some cardiovascular risks.
However a 2005 study found that 5 mg of folate daily over a three-week period reduced pulse pressure by 4.7 mmHg compared with a placebo, and concluded that
- Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.
Also, as a result of new research, "heart experts" at Johns Hopkins Medical Center reported in March 2008 in favour of therapeutic folate, although they cautioned that it is premature for people to begin to self-medicate by taking high doses of folic acid."
Hyperhomocysteinemia is a predictor of cardiovascular disease and hypertension among children and folic acid is a safe and effective supplement because it reduces serum homocysteine levels as well as systolic and diastolic blood pressure, thus preventing cardiovascular disease in children.
Folic acid supplements may improve the integrity of the vascular endothelium.
Folic acid supplements consumed before and during pregnancy may reduce the risk of heart defects in infants.
Folic acid supplementation may reduce the risk of children developing metabolic syndrome.
Folic acid supplements may worsen the outcomes in patients with cardiovascular disease such as angina and myocardial infarction.
Stroke
Folic acid appears to reduce the risk of stroke. The reviews indicate only that in some individuals the risk of stroke appears to be reduced, but a definite recommendation regarding supplementation beyond the current recommended daily allowance has not been established for stroke prevention. Observed stroke reduction is consistent with the reduction in pulse pressure produced by folate supplementation of 5 mg per day, since hypertension is a key risk factor for stroke. Folic supplements are inexpensive and relatively safe to use and that is why stroke or hyperhomocysteinemia patients are encouraged to consume daily B vitamins including folid acid.
Cancer
Folate deficiency decreases intracellular S-adenosylmethionine (SAM) which inhibits cytosine methylation in DNA, activates proto-oncogenes, induces malignant transformations, causes DNA precursor imbalances, misincorporates uracil into DNA, and promotes chromosome breakage; all of these mechanisms increase the risk of prostate cancer development.
The association between folate and cancer appears to be complex. Even though theoretically it has been suggested that folate may help prevent cancer actual trials have found that supplementation increases rates of cancer. Folate has shown to play a dual role in cancer development; low folate intake protects against early carcinogenesis but high folate intake promotes advanced carcinogenesis. Therefore public health recommendations should be careful not to encourage too much folate intake. while other studies find that folate from supplements is more effective due to greater bioavailability. A 2007 randomized clinical trial found that folate supplements did not reduce the risk of colorectal adenomas, but do in fact increase the presence of advanced lesions and adenoma multiplicity. Colorectal cancer is the most studied type of cancer in relation to folate and one carbon metabolism and most research studies associate high folate intake with a reduced risk of prostate cancer. However folic acid supplement intake increased advanced colorectal cancer development by 67% in a 14 year European research study involving 520,000 men.
A 2006 prospective study of 81,922 Swedish adults found that diets great in folate from foods, but not from supplements, were associated with a reduced risk of pancreatic cancer.
Most epidemiologic studies suggest that diets high in folate are associated with decreased risk of breast cancer, but results are not uniformly consistent: one broad cancer screening trial reported a potential harmful effect of much folate intake on breast cancer risk, suggesting that routine folate supplementation should not be recommended as a breast cancer preventive, but a 2007 Swedish prospective study found that much folate intake was associated with a lower incidence of postmenopausal breast cancer. A 2008 study has shown no significant effect of folic acid on overall risk of total invasive cancer or breast cancer among women. Folate intake may not have any effect on the risk of breast cancer but may have an effect for women who consume at least 15 g/d of alcohol. Folate intake of more than 300 µg/d may reduce the risk of breast cancer in women who consume alcohol. Recently a clinical trial showed that daily supplementation of 1 mg of folic acid increased the risk of prostate cancer while dietary and plasma folate levels among non vitamin users actually decreased the risk of prostate cancer. The reasons why high levels of folic acid may increase cancer is because of its role in nucleotide synthesis (proliferating neoplastic cells need this and folate receptors are increased in cancers). Folate's role in DNA methylation is important in prostate cancer. Unmetabolized folic acid is associated with a reduction in natural killer cell cytotoxicity which reduces the immune system's ability to defend against malignant cells. However, the study also showed that dietary baseline intake of folate may have inverse effects of prostate cancer.
The cancer drug methotrexate is designed to inhibit the metabolism of folic acid. Folic acid may interact unexpectedly with the cancer drug fluorouracil. The exact mechanism of interaction is unknown.
The low dihydrofolate reductase activity in the liver of humans compared to other animals and so the low conversion of folic acid into its active derivatives might be due to the control of this enzyme by transcription factors such as E2F-1 involved in cell proliferation. It has been suggested that "the low level of DHFR, and the other proteins under the control of E2F-1, in humans may have evolved to hinder the development of cancer. If this is the case, other animals with slow tissue turnover rates, possibly related to long life span, might also have low DHFR activity. Growth of tumor cells are significantly inhibited when a folate-linked nanoparticle is injected intratumorally. This is a proposed mechanism for folic acid's protection against colorectal cancer. Folic acid may also reduce the levels of PTEN (a tumor suppressor gene), making this relationship even more controversial.
producing side effects such as inflammation in the digestive tract that make it difficult to eat normally. Also, bone marrow depression (inducing leukopenia and thrombocytopenia), acute renal and hepatic failure have been reported.
Folinic acid, under the drug name leucovorin, is a form of folate (formyl-THF) that can help "rescue" or reverse the toxic effects of methotrexate.
Folinic acid is ''not'' the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.
There have been cases of severe adverse effects of accidental substitution of folic acid for folinic acid in patients receiving methotrexate cancer chemotherapy. It is important for anyone receiving methotrexate to follow medical advice on the use of folic or folinic acid supplements. The supplement of folinic acid in patients undergoing methotrexate treatment is to give non rapidly dividing cells enough folate to maintain normal cell functions. The amount of folate given will be depleted by rapidly dividing cells (cancer) very fast and so will not negate the effects of methotrexate.
Low dose methotrexate is used to treat a wide variety of non-cancerous diseases such as rheumatoid arthritis, lupus, scleroderma, psoriasis, asthma, sarcoidosis, primary biliary cirrhosis, polymyositis, and inflammatory bowel disease.
Low doses of methotrexate can deplete folate stores and cause side effects that are similar to folate deficiency. Both high folate diets and supplemental folic acid may help reduce the toxic side effects of low dose methotrexate without decreasing its effectiveness.
Anyone taking low dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.
While the role in folate as a cancer treatment is well established its long term effectiveness is diminished by cellular response. In response to decreased THF the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase increased concentrations of DHF reductase can overcome the drugs inhibition.
Obesity
Folic acid increases lipolysis in adipocytes and may have a role in the prevention of obesity and type 2 diabetes. This mechanism involves the beta adrenoreceptors in the adbdominal adipocytes.
Folic acid supplements may reduce the accumulation of cholesterol in the liver and in the blood; this may be due to folic acid's role in incorporating cholesterol into bile acid. In fact folic acid supplements have been shown to increase bile acid production and flow.
Depression
Some evidence links a shortage of folate with depression.
There is some limited evidence from randomised controlled trials that using folic acid in addition to antidepressants, specifically SSRIs, may have benefits. Research at the University of York and Hull York Medical School has found a link between depression and low levels of folate. One study by the same team involved 15,315 subjects. However, the evidence is probably too limited at present for this to be a routine treatment recommendation.
Folic acid supplements have an effect on noradrenaline and serotonine receptors in the brain and this relationship may be the reason why folic acid is an antidepressant.
Memory and mental agility
In a 3-year trial on 818 people over the age of 50, short-term memory, mental agility, and verbal fluency were all found to be better among people who took 800 micrograms of folic acid daily, twice the current RDA, than those who took placebo. The study was reported in ''The Lancet'' on 20 January 2007.
Schizophrenia
Folate deficiency may increase the risk of schizophrenia because by increasing homocysteine levels folate also increases interleukin 6 and tumor necrosis factor alpha levels and these two cytokines are involved in the development of schizophrenia. The exact mechanisms involved in the development of schizophrenia are not entirely clear but may have something to do with DNA methylation and one carbon metabolism and these are the precise roles of folate in the body and that is why folate deficiency has been linked to schizophrenia.
Allergic diseases
There is a relationship between folic acid and allergic diseases. In one study that examined the relationship between serum folate levels and markers of atopy, wheeze, and asthma in 8083 subjects serum folate levels were found to be inversely related to IgE level, atopy, and wheeze in a dose-response relationship. Increased folate levels were also associated with decreased risk of doctor-diagnosed asthma. Folic acid supplementation during late pregnancy is associated with an increased risk of childhood asthma, increased risk of persistent asthma, and poorer respiratory function in young children.
Rheumatoid arthritis
Folic acid supplementation of 5–27 mg per week has shown to have a protective effect against rheumatoid arthritis.
Fertility
Folate is necessary for fertility in both men and women. In men, it contributes to spermatogenesis. In women, on the other hand, it contributes to oocyte maturation, implantation, placentation, in addition to the general effects of folic acid and pregnancy. Therefore, it is necessary to receive sufficient amounts through the diet, in order to avoid subfertility.
Renal disease
Folic acid supplements may reduce the risk of children developing renal diseases or injuries such as microalbuminuria.
Type 1 diabetes mellitus
Type 1 diabetes mellitus patients have lower plasma levels of folic acid and may benefit from folic acid supplements or folic acid fortified food products.
Macular degeneration
A substudy of the Women's Antioxidant and Folic Acid Cardiovascular Study published in 2009 reports that use of a nutritional supplement that contains folic acid, pyridoxine, and cyanocobalamin decreased the risk of developing age-related macular degeneration by 34%.
Bone health
It has been hypothesized that folate deficiency can lead to elevated homocysteine levels which in turn lead to an increased risk of bone fractures, osteoporosis, and reduction in BMD but research studies so far show controversial results.
Menopause
Folic acid supplements help relieve hot flushes in postmenopausal women.
Bone loss in Parkinson's disease (PD)
Folate lowers homocysteine (Hcy) levels which in turn prevents bone loss in Parkinson's disease (PD) patients taking levodopa (a psychoactive drug taken to treat Parkinson's disease). Improvements in bone health include increased BMD at the lumbar spine, total femur, and femur shaft.
Folic acid supplements and masking of B12 deficiency
There has been concern about the interaction between vitamin B12 and folic acid. Folic acid supplements can correct the anemia associated with vitamin B12 deficiency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated. Therefore, intake of supplemental folic acid should not exceed 1000 micrograms (1000 µg or 1 mg) per day to prevent folic acid from masking symptoms of vitamin B12 deficiency. In fact, to date the evidence that such masking actually occurs is scarce, and there is no evidence that folic acid fortification in Canada or the U.S. has increased the prevalence of vitamin B12 deficiency or its consequences.
However, one recent study has demonstrated that high folic or folate levels, when combined with low B12 levels, are associated with significant cognitive impairment among the elderly.
In any case, it is important for older adults to be aware of the relationship between folic acid and vitamin B12, because they are at greater risk of having a vitamin B12 deficiency. Patients 50 years of age or older should ask their physicians to check their vitamin B12 status before taking a supplement that contains folic acid.
Health risk of too much folic acid
The risk of toxicity from folic acid is low because folate is a water soluble vitamin and is regularly removed from the body through urine.
The Institute of Medicine has established a tolerable upper intake level (UL) for folate of 1 mg for adult men and women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18 years of age. Supplemental folic acid should not exceed the UL to prevent folic acid from masking symptoms of vitamin B12 deficiency.
Research suggests high levels of folic acid can interfere with some antimalarial treatments.
A 10,000-patient study at Tufts University in 2007 concluded that excess folic acid worsens the effects of B12 deficiency and in fact may affect the absorption of B12.
A study at the University of Adelaide concluded that the intake of folic acid supplements during late pregnancy increases the risk of babies developing childhood asthma by 30%, although researchers emphasized that their finding did not contradict recommendations to supplement folic acid in first trimester, when no additional risk was found.
Elderly population
There are benefits and risks of food folic acid fortification for elderly populations. Elevated exposure to folic acid due to fortification can improve folate and homocysteine levels but can also mask symptoms of vitamin B12 deficiency. Folate deficiency is diagnosed by analyzing CBC and plasma vitamin B12 and folate levels.
Patients with celiac disease have a higher chance of developing folate deficiency.
Cobalamin deficiency may lead to folate deficiency which in turn increases homocysteine levels and finally may result in the development of cardiovascular disease or birth defects.
Folic acid supplementation risk for children
Some studies show that folic acid supplementation in children may result in the development of malaria and increased mortality; this has prompted the World Health Organization to alter their supplementation policies for children in areas like India.
Further Reading
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